Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, with an estimated 23 million people who suffer from it. At present, no effective treatment exists to halt the decline in lung function in response to smoking. This in turn reflects a lack of understanding of the specific cellular and biochemical pathways triggered in the lung by tobacco smoke. Cigarette smoke (CS) triggers inflammation which plays a central role in the development of COPD by a mechanism mediated via enhanced pro-inflammatory gene transcription. However, very little is known about the molecular mechanisms whereby cigarette smoke triggers abnormal and sustained lung inflammation. Histone acetylation and deacetylation comprise a key regulator of the specificity and duration of gene transcription. Alteration in the overall balance between nuclear histone acetylation: deacetylation (chromatin remodeling), and/or in acetylation patterns at specific promoters can result in aberrant transcription of pro-inflammatory genes in the lungs. We have demonstrated that CS activates I(B-kinase (IKK)-1 and causes increased histone acetylation as well as acetylation of the RelA/p65 subunit of NF(B in primary human small airway epithelial cells (SAEC) and in mouse lung leading to increased levels of pro-inflammatory cytokines. However, the molecular mechanisms of IKK1 activation and its involvement in acetylation of histones, acetylation of RelA/p65, and decrease in histone deacetylase (HDAC) activity in response to CS remain unknown. We hypothesize that CS triggers activation of I(B kinase-1 (IKK1) via NF(B-inducing kinase (NIK) leading to acetylation of histone proteins and of the RelA/p65 subunit of NF(B at the promoters of pro-inflammatory genes in lung epithelium. Furthermore, CS suppresses HDAC, particularly HDAC2, by altered kinase signaling and/or by post-translational modifications (ubiquitination-degradation). This leads to prolonged and sustained induction of NF(B-driven pro-inflammatory genes in the lungs. To test this hypothesis, we propose the following three aims: Aim 1: To determine the role of IKK1 in cigarette smoke-mediated histone acetylation in primary human SAEC in vitro and in mouse lungs in vivo. Aim 2: To determine the mechanisms of acetylation of RelA/p65 and the role of this modification in recruitment of CREB-binding protein (CBP) to target gene promoters. Aim 3: To determine the molecular mechanisms by which CS exposure results in down-regulation of HDAC2 in primary human SAEC and in mouse lungs. These studies are designed to identify the transcriptional regulatory processes that are altered by CS exposure leading to abnormal lung inflammation, and determine the role of IKK1 in acetylation of histone proteins. The experiments outlined in this proposal will also identify key intracellular signaling events in the histone acetylation/deacetylation pathway and will allow us to identify therapeutic targets for cigarette smoke-mediated abnormal lung inflammation. Impact on public health: Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, with an estimated 23 million people who suffer from it. At present, there is no effective treatment to halt the decline in lung function in response to smoking. Using a variety of models, our research will identify the key intracellular molecular signaling events in inflammatory pathway and will allow us to identify therapeutic targets for cigarette smoke-mediated abnormal sustained lung inflammation and injury.